Stuck in the middle: structural insights into the role of the gH/gL heterodimer in herpesvirus entry - PubMed (original) (raw)

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Stuck in the middle: structural insights into the role of the gH/gL heterodimer in herpesvirus entry

Samuel D Stampfer et al. Curr Opin Virol. 2013 Feb.

Abstract

Enveloped viruses enter cells by fusing the viral and cellular membranes, and most use a single viral envelope protein that combines receptor-binding and fusogenic functions. In herpesviruses, these functions are distributed among multiple proteins: the conserved fusion protein gB, various non-conserved receptor-binding proteins, and the conserved gH/gL heterodimer that curiously lacks an apparent counterpart in other enveloped viruses. Recent structural studies of gH/gL from HSV-2 and EBV revealed a unique complex with no structural or functional similarity to other viral proteins. Here we analyzed gH/gL structures and highlighted important functional regions. We propose that gH/gL functions as an adaptor that transmits the triggering signals from various non-conserved inputs to the highly conserved fusion protein gB.

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Figures

Fig. 1

Fig. 1

Structural similarities between HSV and EBV gH/gL. (a) Structures of HSV-2 gH/gL (PDB: 3M1C) [8] and EBV gH/gL (PDB: 3PHF) [9] are colored by domain, and all domains are labeled. (b) Aligned individual domains are shown side by side and labeled. Color scheme matches that in (a). HSV-2 gH domains are shown in the same orientation as in (a). EBV gH domains are aligned onto HSV domains and are shown in the same orientation. HSV Domains: H1A: 19-120, H1B: 121-331, H2A: 332-441, H2B: 442-645, H3: 646-797. EBV Domains: H1A: 19-48, H1B: 49-238, H2A: 239-344, H2B: 345-527, H3: 528-677. (c-d) HSV-2 and EBV gL share structural similarities with chemokines. (c) Chemokine folds of HSV-2 and EBV gL (blue) align well with the CC chemokine CCL3 (orange, PDB: 2X6G-P) [45] (orange) and other chemokines (not shown) using DALI [46]. Disulfides are shown in green. Non-chemokine-fold regions in all three molecules are shown using lighter shades. (d) A continuous intermolecular β-sheet in IL8 homodimer is mimicked in gH/gL heterodimer. IL8 monomers are shown in orange and cyan, HSV-2 gH/gL and EBV gH/gL are shown using the same colors as in (a) and (b). Intermolecular sheets are outlined. All structures were made using Pymol (

http://www.pymol.org

). Alignments were carried out using Coot [47].

Fig. 2

Fig. 2

Functional sites in HSV-2 and EBV gH/gL. HSV-1 gH/gL (a) and EBV gH/gL (b) are shown using wireframe representation and paler colors than in Fig. 1. An extended polypeptide in H3, the “flap”, is shown as a thick tube. Disulfide bonds that anchor it are shown in green, and key functional residues, in purple. (a) Functional sites in HSV gH/gL. Residues that define the LP11 epitope are shown in blue (mar mutations [43]) and insertions that block LP11 binding [17] are shown in cyan. The putative gB-binding site [8] is outlined. A RGD motif is shown in magenta. (b) Functional sites in EBV gH/gL. A KGD motif (magenta) is the putative binding site for integrins and gp42 as both are affected by mutations in the KGD motif [39]. gL residues Q54 and K94 within the putative gB activation site [44] (outlined) are shown in blue. (c) Proposed mechanism of fusion inhibition by anti-HSV-1-gH/gL mAb 52S. Binding of gB in a conserved groove (outlined) displaces a stack of α helices (shown as ribbons) and impinges on the 52S epitope. Arrow indicates the hypothetical direction of the displacement. Concomitant conformational changes may allow gH/gL to bend around gB, delivering an activation signal to gB. Binding of 52S antibody may prevent such dislocation and thus transmission of the activation signal. Residues mutated in 52S mar mutant [43] are shown in green; the putative gB-binding site in gH/gL is outlined. The fusion-null mutation in VZV gH/gL (red) marks the region that may be involved in transmitting the gB-activating intramolecular signal within gH/gL.

Fig. 3

Fig. 3

A variety of receptor inputs are transmitted through gH/gL to the conserved fusion protein gB. Cell entry machinery of HSV-2 (top) and EBV (bottom). All crystal structures are shown in surface representation. Top: HSV-1 gD/HVEM (PDB: 1JMA) [29], HSV-1 gD/nectin (PDB: 3SKU) [30], HSV-2 gH/gL (PDB: 3M1C) [8], and HSV-1 gB (PDB: 2GUM) [4]. Bottom: EBV gp42/HLA-DR1 (PDB: 1KG0) [31], αVβ3 integrin (PDB: 3IJE) [48], (used in place of αVβ5, αVβ6, and αVβ8, for which no structures are available), EBV gH/gL (PDB: 3PHF) [9], and EBV gB (PDB: 3FVC) [49].

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